Autoimmune-mediated destruction of [unreadable]-cells is the predominant cause of Type 1 diabetes mellitus (T1 DM). Current therapy, based on the replacement of [unreadable]-cells through islet transplantation and subsequent immune suppression, has significant limitations. In this proposal we focus on the natural ability of [unreadable]-cells to regenerate and restore glucose homeostasis in a mouse model of diabetes. The long-term goal of this project is to utilize the natural ability of [unreadable]-cells to regenerate as an innovative approach for the treatment of T1DM. This project represents a continuation of collaborative studies between the Chong, Philipson and Fu laboratories. Little is known about the capacity of regenerated islets to reproduce the normal physiological function of [unreadable]-cells and maintain glucose homeostasis after the development of overt diabetes. We have developed a new model of islet regeneration that will enable us to systematically define key mechanisms in [unreadable]-cell restoration. Our preliminary experiments demonstrate restoration of functional [unreadable]-cell mass and blood glucose regulation following an induced destruction of adult mouse [unreadable]-cells with high-dose streptozotocin (STZ). We also observed a significant requirement for splenocytes in islet cell regeneration after high-dose STZ treatment. [unreadable] [unreadable] The cellular and molecular basis for how splenocytes enhance [unreadable]-cell regeneration is not known. Published results have suggested that the signals triggering liver regeneration also trigger [unreadable]-cell proliferation and regeneration. Recent studies by Fu laboratory have revealed a novel role of T lymphocytes and lymphotoxin-[unreadable] (LT[unreadable]) signaling in facilitating liver regeneration. In this proposal, we will test the overall hypothesis that the cellular and soluble or cell membrane factors stimulating liver regeneration also stimulate [unreadable]-cell regeneration. The Specific Aims are to: Specific Aim 1. Test the hypothesis that T lymphocytes are the critical cell subset in the spleen regulating the regeneration of [unreadable] [unreadable]-cells in vivo. We will compare the rate of [unreadable]-cell regeneration in C57BL/6 mice lacking T cells, and made diabetic with STZ. We will also test whether splenocytes depleted of T cells have reduced efficacy in stimulating [unreadable]-cell regeneration in splenectomized, diabetic mice. Specific Aim 2. Test the hypothesis that lymphotoxin-beta receptor (LT[unreadable]R) signaling plays a critical role in stimulating [unreadable]-cell regeneration in vivo. We will test whether the rate of [unreadable]-cell regeneration is reduced when signaling through the LT[unreadable]R is prevented by soluble LT[unreadable]R (sLT[unreadable]R) or in LT[unreadable]R deficient mice. We will also test whether expression of the ligands of LT[unreadable]R, LTa[unreadable] or LIGHT, on spleen cells and LT[unreadable]R on islet [unreadable]-cells is critical for stimulating [unreadable]-cell regeneration. [unreadable] [unreadable]